Reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA)

ABSTRACT

Methods of reducing post-prandial fluctuations in plasma levels of large, neutral amino acids (LNAA), as well as compositions useful in that method. The compositions comprise a carbohydrate to protein ratio of from about 3:1 to about 10:1 and, in a specific embodiment, a ratio of 7:1, which results in minimizing the variability in responses which individuals exhibit to drugs which are LNAA.

This is a continuation of application Ser. No. 08/029,505, filed Mar. 11, 1993, now abandoned, which is a continuation-in-part of application Ser. No. 07/849,246, filed Mar. 11, 1992, now abandoned, which was a continuation-in-part of application Ser. No. 07/332,871, filed Apr. 3, 1989, now U.S. Pat. No. 5,206,218, each of which is hereby incorporated by reference in its entirety.

BACKGROUND

Treatment of some diseases, such as Parkinson's Disease, includes administration of a drug which is a large neutral amino acid (LNAA) and which must cross the blood-brain barrier to be effective. For example, L-dopa, alphamethyldopa (ALDOMET) and 5-hydroxytryptophan, which are LNAA, can be administered in the treatment of Parkinson's Disease, hypertension or myoclonus. Patients who take such drugs may exhibit variability in their responses to them and may suffer adverse effects, such as L-Dopa induced dyskinesia, from them.

It would be useful to have a means by which an individual's response to such drugs can be controlled and the adverse effects reduced.

SUMMARY OF THE INVENTION

The present invention pertains to a method of reducing post-prandial fluctuations in plasma LNAA levels in an individual, particularly for the purpose of reducing variability in the individual's response to treatment with drugs which are themselves LNAA. It further relates to compositions for administration to an individual to reduce fluctuations in plasma concentrations of large neutral amino acids (LNAA). As used herein, LNAA includes amino acids which have a single amino group and a single carboxyl group, for example, leucine, isoleucine, tyrosine, valine, phenylalanine and tryptophan.

The present composition comprises an appropriate ratio of carbohydrates to protein to reduce fluctuations in plasma LNAA levels, when administered to an individual. The ratio of carbohydrate to protein used can vary from about 3:1 to about 10:1, depending on the individual to whom such a composition is administered, with a ratio 7:1 having been found to be particularly effective. Such characteristics as body weight and plasma amino acid responses are to be considered in determining an appropriate carbohydrate to protein ratio for an individual. The present invention also relates to methods of administering foods or compositions which minimize post-prandial fluctuations in plasma LNAA levels. Administration of such compositions or of foods selected to contain a carbohydrate to protein ratio of from about 3:1 to about 10:1 is particularly valuable in minimizing the variability in responses some individuals exhibit to drugs, such as L-dopa, which are themselves LNAA. If an individual wishes to minimize fluctuations in plasma LNAA for only a segment of the twenty-four hour day, the present method can be used to determine the composition of meals and/or snacks consumed during that segment.

For example, foods which provide about 80-500 grams of carbohydrate per day and 7-100 grams of protein per day can be administered to an individual suffering from Parkinson's disease who is being treated with L-dopa and whose response to the drug varies and may be associated with adverse effects, such as dyskinesia.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery that fluctuations in plasma LNAA levels, particularly post-prandial fluctuations, can be reduced or controlled and, as a result, that the variability in response in an individual to administration of a drug or drugs which is/are LNAA can also be reduced or controlled. The ability to reduce plasma LNAA level fluctuation and, concomitantly, variation in response to a drug which is a LNAA is of particular value in the management of individuals, such as those with Parkinson's disease, who take such a drug or drugs for treatment of a disease or other condition. It is now possible to improve treatment of individuals taking LNAA because the adverse effects can be ameliorated or eliminated and, as a result, individuals are able to continue to follow their prescribed treatment.

It is known that post-prandial plasma levels of LNAA can vary widely and that such levels are affected by the carbohydrate and protein content of foods consumed.

Fernstrom et al. report that plasma leucine was 60 nmoles/ml after a protein-free, high carbohydrate breakfast, and about 240 nmoles/ml after a high protein breakfast. Plasma valine varied from about 100 nmol/ml to 50 nmols/ml under these conditions, and plasma isoleucine ranged from 30 to 60 nmols/ml. Am J. Clin. Nutr., 32:1912-1922 (1979). A meal rich in carbohydrates elicits the secretion of insulin and facilitates the passage of LNAA out of the blood stream and into peripheral tissues, thus reducing circulating levels. In contrast, a meal rich in protein tends to increase blood levels of LNAA. Some of the LNAA in the protein passes right through the liver, without being metabolized, and into the systemic circulation.

These fluctuations normally are important determinants of brain levels of one of the LNAA, tryptophan, and thus of the formation of the neurotransmitter serotonin from tryptophan. This is due to the fact that all of the LNAA in the plasma must compete for access to a common transport system in order to be transported across the blood-brain barrier. Therefore, a high-protein meal will tend to diminish brain tryptophan because it causes blood levels of the other LNAA to increase more, proportionately, than those of tryptophan. In contrast, a high-carbohydrate meal will tend to increase brain tryptophan and serotonin levels because insulin secreted in response to the carbohydrates lowers the other LNAA.

Post-prandial changes in plasma LNAA are also important determinants of brain levels of drugs which are themselves LNAA and must compete with other LNAA for transport across the blood-brain barrier. There are a number of diseases which are treated with drugs, such as L-dopa, that compete with circulating large neutral amino acids (LNAA) for passage from the blood stream into the brain. L-dopa and such other drugs as alphamethyldopa (ALDOMET) and 5-hydroxytryptophan which are themselves LNAA, must enter the brain in order to be effective. Brain levels of one such drug, L-dopa, are known to vary with the plasma dopa ratio (i.e., the ratio of plasma dopa concentration to the summed concentrations of the other LNAA) and not with the dopa concentration alone. See Markovitz et al., Science 197: 1014-1015 (1977). Patients who take such drugs may exhibit variability in response to them, as well as adverse effects, such as dyskinesia.

It has now been shown that these post-prandial fluctuations in plasma LNAA can be controlled or reduced and, as a result, variability in the clinical responses to treatment with drugs which are LNAA can also be reduced or eliminated.

The present invention relates to a method for reducing fluctuations in plasma levels of large neutral amino acids and to compositions and combinations of foods having a selected carbohydrate to protein ratio for use in treating individuals who exhibit variability in responses to drugs, such as L-dopa, which are themselves LNAA, and which must enter the brain in order to be effective. The term LNAA, as used herein, includes amino acids which comprise a single amino acid and a single carboxyl group such as leucine, isoleucine, valine, tyrosine, phenylalanine, and tryptophan. Use of the method of the present invention with an individual who is taking a drug (or drugs) which is an LNAA makes it possible to reduce the fluctuations in post-prandial plasma levels of LNAA. That is, it makes it possible to control the post-prandial LNAA levels in such a manner that they exhibit less variation than is evident when the individual being treated consumes his or her "usual" diet.

In one embodiment of the present invention, a composition in which the carbohydrate to protein ratio is approximately 7:1 is administered to a group of individuals. Depending on the individual, the ratio of carbohydrate to protein can vary from about 3:1 to about 10:1. For example, for individuals with reduced insulin sensitivity (i.e., secondary to type II diabetes, obesity, or elevated lean body mass), it may be necessary to provide a larger total amount or higher proportion of dietary carbohydrate, in order to balance the protein-induced rise in plasma LNAA, or to reduce the percent of dietary protein.

In another embodiment, foods for meals or snacks can be prepared which provide an effective carbohydrate to protein ratio to minimize post-prandial fluctuations in plasma concentrations of LNAA. Foods which provide approximately 80-500 grams of carbohydrate per day or 80-116 grams of carbohydrate per meal and approximately 7-100 grams of protein per day or 7-27 grams of protein per meal can be administered to an individual. For example, approximately 250 grams of carbohydrate per day and approximately 35 grams of protein per day will minimize fluctuations in plasma LNAA levels. The actual quantity (or range of quantities) of carbohydrate and of protein to be administered to an individual will be determined empirically, by determining the proportion that elicits the optimal clinical response (i.e., greatest drug response and fewest side effects). If necessary, the optimal amounts of carbohydrates and protein can be affirmed by testing their effects on plasma LNAA levels and ratios. The LNAA measured are leucine, isoleucine, valine, tyrosine, phenylalanine and tryptophan. The post-prandial changes are measured between 1 and 5 hours after the meal or snack has been consumed. Assessment of values obtained in this manner make it possible to determine an appropriate carbohydrate to protein ratio for an individual (i.e., one effective in reducing or eliminating fluctuations in plasma LNAA levels and, concomitantly, in reducing or eliminating variable responses to a drug, such as L-dopa, which is a LNAA). For purposes of calculation, the carbohydrates in the foods may be normalized in terms of their ability to trigger insulin release (foods with a high glycemic index include among others potato, starch or sucrose). A preferred embodiment utilizes a combination of maltodextrin and sucrose.

According to the method of the present invention, compositions or foods comprising an effective carbohydrate to protein ratio can be administered to individuals to minimize the variability in clinical responses to treatment with drugs which are LNAA. For example, drugs such as L-dopa (levodopa), alphamethyldopa (ALDOMET), and 5-hydroxytryptophan are LNAA and must compete with other LNAA for transport across the blood-brain barrier.

The present invention will now be illustrated by the following Exemplifications, which are not intended to be limiting in any way.

EXEMPLIFICATION I Assessment of plasma levels of LNAA after consumption of a composition with a 7:1 ratio of carbohydrate to protein

The subjects were 12 healthy individuals, 6 males and 6 females, between the ages of 56 and 72 years (average age: 67.6 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 7:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels.

As shown in Table I, at one hour after consumption of the 7:1 beverage, the mean level of LNAA for all individuals was 7% higher than the mean fasting level of LNAA. At three hours post-consumption, the mean level was 3% higher.

                  TABLE I                                                          ______________________________________                                                 FASTING LNAA  ONE HOUR   THREE HOUR                                    SUBJECT LEVEL         LNAA LEVEL LNAA LEVEL                                    ______________________________________                                          1      540           579        621                                            2      610           571        612                                            3      462           597        420                                            4      615           698        526                                            5      521           497        483                                            6      429            44        573                                            7      488           507        519                                            8      448           485        574                                            9      475           554        529                                           10      453           500        451                                           11      541           534        413                                           12      432           492        463                                           MEAN    501           538        515                                           S.E.M.   19            19         20                                           % CHANGE               7          3                                            ______________________________________                                    

EXEMPLIFICATION II Assessment of plasma levels of LNAA in Parkinsons patients after consumption of a composition with a 7:1 ratio of carbohydrate to protein

The subjects were 7 individuals with Parkinson's Disease, 4 males and 3 females, between the ages of 57 and 79 years (average age: 66.3 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 7:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels.

As shown in Table III, at one hour after consumption of the 7:1 beverage, the mean level of LNAA for all individuals was 19% higher than the mean fasting level of LNAA. At three hours post-consumption, the mean level was 3% lower than the mean fasting level of LNAA.

                  TABLE II                                                         ______________________________________                                                 FASTING LNAA  ONE HOUR   THREE HOUR                                    SUBJECT LEVEL         LNAA LEVEL LNAA LEVEL                                    ______________________________________                                         13      558           740        428                                           14      486           588        602                                           15      649           783        583                                           16      619           586        586                                           17      458           548        573                                           18      601           777        509                                           19      570           660        532                                           MEAN    563           669        545                                           S.E.M.   26            37         23                                           % CHANGE               19         -3                                           ______________________________________                                    

EXEMPLIFICATION III Assessment of plasma levels of LNAA in Parkinsons patients after consumption of a composition with a 10:1 ratio of carbohydrate to protein

The subjects were 7 individuals with Parkinson's Disease, 4 males and 3 females, between the ages of 57 and 79 years (average age: 66.3 years). Blood was drawn for a determination of the fasting blood levels of LNAA, in each individual, prior to ingestion of a beverage containing a 10:1 ratio of carbohydrate to protein. Blood was then drawn at one (1) hour and three (3) hours post-consumption for determination of LNAA levels.

As shown in Table III, at one hour after consumption of the 10:1 beverage, the mean level of LNAA for all individuals was 8% higher than the mean fasting level of LNAA. At three hours post-consumption, the mean level was 8% lower than the mean fasting level of LNAA.

                  TABLE III                                                        ______________________________________                                                 FASTING LNAA  ONE HOUR   THREE HOUR                                    SUBJECT LEVEL         LNAA LEVEL LNAA LEVEL                                    ______________________________________                                         13      630           651        554                                           14      534           526        545                                           15      632           722        563                                           16      675           706        619                                           17      600           623        579                                           18      575           738        516                                           19      533           561        481                                           MEAN    597           647        551                                           S.E.M.   20            31         17                                           % CHANGE               -8         8                                            ______________________________________                                    

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiment of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. 

What is claimed is:
 1. A method of reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA), comprising administering to an individual a composition comprising a carbohydrate to protein ratio of from approximately 7:1 to approximately 10:1, in an amount effective to reduce post-prandial fluctuations.
 2. A method according to claim 1, wherein the LNAA are selected from the group consisting of: leucine, isoleucine, valine, tyrosine, phenylalanine, and tryptophan.
 3. A method according to claim 1, wherein the ratio of carbohydrate to protein is approximately 7:1.
 4. A method of reducing post-prandial fluctuations in plasma concentrations of large neutral amino acids (LNAA), comprising administering to an individual foods which provide a ratio of carbohydrate to protein of from approximately 7:1 to approximately 10:1.
 5. A method according to claim 4, wherein the LNAA are selected from the group consisting of: leucine, isoleucine, valine, tyrosine, phenylalanine, and tryptophan.
 6. A method according to claim 4, wherein the ratio of carbohydrate to protein is approximately 7:1. 